Cushing syndrome, a fatal disease, is suspected in many thousands of patients each year, but confirmed in only a fraction of these. This project seeks to identify accurately which patients have Cushing syndrome, to define the etiology of their disease and to treat it optimally. We are exploring quality-of-life issues in patients before and after successful treatment of Cushing's syndrome. We use the entire SF-36 questionnaire developed by John Ware and colleagues; the questionnaire has been validated for use in healthy individuals and various disease states. Patients also complete a symptom checklist and a questionnaire about recurrence, satisfaction with treatment, current treatment, and demographics. We found that patients with active Cushing's syndrome have great impairment in physical activities and cognitive function and that they also limit social activities. Patients also demonstrate significant but less profound abnormalities in their sense of well-being and general health perception compared with the general population. Quality of life improves in the first five years after treatment, but some areas remain subnormal for up to fifteen years after treatment, suggesting significant long-term impairment of quality of life in these individuals. Ectopic, non-pituitary corticotropin (ACTH) secretion (EAS) is difficult to diagnose and treat. To evaluate the diagnostic and management strategies for EAS, we retrospectively reviewed our experience with 90 patients admitted from 1983-2004. Tests included 8 mg dexamethasone suppression (DST), corticotropin-releasing hormone (CRH) stimulation, inferior petrosal sinus sampling (IPSS), computed tomography, octreotide scan, magnetic resonance imaging and/or venous sampling. Eighty-six to 94% of patients did not respond to CRH or DST, while 66/67 had negative IPSS. To control hypercortisolism, 62 patients received medical treatment; 33 patients had bilateral adrenalectomy. Imaging localized potential tumors in 67/90 patients. Surgery confirmed an ACTH-secreting tumor in 60 of 66 patients and cured 65% of them. Non-thymic carcinoids took longest to localize. Deaths included 3/35 with pulmonary carcinoid, 2/5 with thymic carcinoid, 4/6 with gastrinoma (GA), 2/12 with neuroendocrine tumor, 2/2 with medullary thyroid cancer (MTC), 1/5 with pheochromocytoma, 3/3 with small cell lung cancer (SCLC) and 2/16 with occult tumor. Patients with other carcinoids and ethesioneuroblastoma are alive. We conclude that IPSS best identifies EAS. Initial failed localization is common, suggests pulmonary carcinoid, and has a favorable prognosis. While only 41/90 of patients (46%) achieved cure, overall survival is good except in patients with SCLC, MTC and GA. Imaging studies are the cornerstone for tumor localization in patients with Cushing's syndrome caused by ectopic adrenocorticotropin hormone (ACTH) secretion (EAS). Computed tomography (CT) and magnetic resonance imaging (MRI) are used most commonly to localize the source of EAS. However, in 30-50 percent of patients with EAS the source of ACTH secretion cannot be found despite repeated studies over time. Up to half of these patients do not respond to medical therapy of hypercortisolism and must undergo bilateral adrenalectomy with lifelong replacement therapy. Thus, there is a need for improved imaging techniques to identify ACTH-secreting tumors. Nuclear medicine techniques enable in vivo imaging of physiological and pathophysiological processes, and among these techniques, positron emission tomography (PET) studies are increasingly used in oncology. We previously evaluated the utility of [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) or [111In-DTPA-D-Phe]-pentetreotide (OCT) at higher than standard doses of radionuclide (18 mCi; H-OCT), and found that FDG-PET did not detect tumors that were occult on CT/MRI. H-OCT rarely identified a lesion. Thus, conventional modalities of CT and MRI should be used to image the neck, thorax, and abdomen in these patients. FDG-PET does not provide additional information. H-OCT may be useful when other imaging modalities fail to localize the ACTH-secreting tumor. We are extending these studies to evaluate the utility of [18F]- L-3,4-dihydroxyphenylalanine (18F-DOPA) PET to identify these tumors. This compound is a precursor for serotonin production in neuroendocrine tumors, and thus is a good candidate for PET examination since most occult ACTH-secreting tumors are neuroendocrine. Recent data suggests that Cushing's syndrome is more common than suspected in populations with a common feature of the disorder, such as diabetes or hypertension. Calls for increased screening in these populations, may result in false positive diagnoses. As weight gain and obesity are nearly universal features of Cushing's syndrome, we hypothesized that these patients should undergo screening, but that screening tests may have poor specificity. The study is based in a weight loss clinic and enrolls individuals with at least two additional signs or symptoms of Cushing's syndrome. Preliminary analysis suggests a high rate (nearly 20%) of falsely positive screening tests in patients who are found to be normal on subsequent confirmatory testing. If confirmed after further study, these results suggest that current recommendations for screening may need revision. Cushing's syndrome occurs rarely during pregnancy. We have investigated and treated four patients with pituitary-dependent Cushing's syndrome during pregnancy over a 15-year period at the NIH. Except for preservation of menses prior to conception, our patients presented with typical clinical features, increased urinary free cortisol, and loss of diurnal variation of cortisol. The diagnosis was facilitated, without complications, by the use of corticotropin-releasing hormone testing and inferior petrosal sinus sampling (IPSS) in three women. Transsphenoidal pituitary surgery (TSS) achieved remission in three women, but there were two fetal/neonatal deaths. This experience and review of 136 previous reports suggest that 1.) UFC in Cushing's syndrome patients overlaps the normal pregnant range, 2.) Adrenocorticotropic hormone (ACTH) levels are not suppressed in adrenal causes of Cushing's syndrome, which may be identified by the 8 mg dexamethasone test, 3.) IPSS and TSS, the optimal diagnostic test and treatment for non-pregnant patients, can safely facilitate the management of pregnant patients and 4.) Surgery may achieve remission during pregnancy, but the prognosis for the fetus remains guarded. It is likely that earlier recognition and treatment would improve outcome. There is a need for development of criteria for interpretation of diagnostic tests and for increased consideration of Cushing's syndrome in pregnancy.